Environmental neurotoxin dieldrin induces apoptosis via caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta): Implications for neurodegeneration in Parkinson's disease.
BACKGROUND
In previous work, we investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons.


METHODS
Here we further investigated dieldrin toxicity in a dopaminergic neuronal cell model of Parkinson's disease, namely N27 cells, using biochemical, immunochemical, and flow cytometric analyses.


RESULTS
In this study, dieldrin-treated N27 cells underwent a rapid and significant increase in reactive oxygen species followed by cytochrome c release into cytosol. The cytosolic cytochrome c activated caspase-dependent apoptotic pathway and the increased caspase-3 activity was observed following a 3 hr dieldrin exposure in a dose-dependent manner. Furthermore, dieldrin caused the caspase-dependent proteolytic cleavage of protein kinase C delta (PKCδ) into 41 kDa catalytic and 38 kDa regulatory subunits in N27 cells as well as in brain slices. PKCδ plays a critical role in executing the apoptotic process in dieldrin-treated dopaminergic neuronal cells because pretreatment with the PKCδ inhibitor rottlerin, or transfection and over-expression of catalytically inactive PKCδ(K)³⁷⁶(R), significantly attenuates dieldrin-induced DNA fragmentation and chromatin condensation.


CONCLUSIONS
Together, we conclude that caspase-3-dependent proteolytic activation of PKCδ is a critical event in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells.
Kanthasamy
Anumantha G
AG
Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, USA. akanthas@iastate.edu
Kitazawa
Masashi
M
Yang
Yongjie
Y
Anantharam
Vellareddy
V
Kanthasamy
Arthi
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D055162:Biocatalysis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004026:Dieldrin / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D061945:Caspase Inhibitors; D004785:Environmental Pollutants; D050505:Mutant Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D051745:Protein Kinase C-delta; D053148:Caspase 3; D004026:Dieldrin